Not All T4 Patients Should Be Considered Equal: Non-Small Cell Lung Cancer Heterogeneity and Surgical Outcome

Stage T4 non-small cell lung cancer (NSCLC) is currently considered to include multifocal tumors in different ipsilateral lobes, local invasion, or tumor size >7 cm. Hence, T4 includes heterogeneous diseases with different oncologic biology that may impact outcomes after surgical resection.

We used the National Cancer Database to examine survival of NSCLC T4 N0-2 M0 after surgical resection between 2010 and 2021 and categorized by 3 T4 subgroups: multifocal, locally invasive, and tumors >7 cm. We used multivariable Cox regression to perform an effect modification analysis between T4 subgroups and nodal stages to evaluate differential association across nodal stages.

Among 27,235 patients with T4 NSCLC, 22.9% had multifocal tumors, 13.9% had locally invasive tumors, and 63.2% had tumors >7 cm. After resection, 5-year survival for multifocal tumors, locally invasive tumors, and tumor size >7 cm was 47.1%, 39.9%, and 39.3%, respectively. Compared with multifocal tumors, locally invasive tumors had 11% higher mortality (hazard ratio, 1.11; P < .001), and tumors >7 cm had 37% higher mortality (hazard ratio, 1.37; P < .001). The association varied across nodal stages. With N0, multifocal tumors had the highest survival, locally invasive tumors had lower survival, and tumors >7 cm had the lowest survival. With N1 or N2, the significant difference between multifocal and locally invasive tumors disappeared, and tumors >7 cm had the worst survival.

Among T4 NSCLC, multifocal tumors had higher survival than tumors >7 cm or locally invasive. The difference between T4 subgroups further varied by nodal stages. Heterogeneity within T4 NSCLC requires better optimization of patient selection to enhance surgical outcomes.